Alcohol abuse is associated with a wide range of cognitive and memory impairments and structural brain changes. The most severe and best recognized types of alcohol-related damage are alcoholic dementia and Wernicke-Korsakoff syndrome. Alcoholism is reportedly diagnosed as the etiologic factor in 7% of all demented patients and alcoholics represent approximately 20% of the admissions to state mental hospitals. Despite the significance of alcohol-related dementias, the etiological roles of alcohol, thiamine deficiency and their interactions remain unclear. Studies of animal models have revealed that long-term exposure of rats to alcohol causes irreversible learning and memory deficits, as well as pathophysiological changes in hippocampal and neocortical cholinergic systems. Other studies have failed to demonstrate behavioral or pathological changes. No studies so far have assessed regional brain thiamine status following prolonged chronic alcohol exposure. Thiamine deficiency alone in humans and animals produces pathologic lesions to thalamus, mammillary bodies, and possibly the neocortex. Recent studies demonstrate that long-term administration of alcohol both impairs intestinal absorption of thiamine and inhibits brain pyrophosphokinase activity necessary for synthesis of the active form of thiamine. The primary goal of the proposed study is to test our hypothesis that neocortical and hippocampal damage is the result of alcohol-induced thiamine deficiency in these structures and related subcortical projection areas. These data will then be used to direct and design more extensive studies of the pathophysiological mechanisms underlying biochemical and pathological changes. The following specific studies will be conducted in rats administered chronic alcohol (32 weeks 20% ETOH in the drinking water) and fed either a thiamine fortified diet or subjected to 3 bouts of thiamine deficiency; l) Following withdrawal and recovery, measure preservation, reference and short-term working memory, and habituation; 2) Determine the levels of thiamine, thiamine esters, and thiamine dependent enzymes in frontal, parietal, and cingulate cortex, hippocampus, septum, thalamus, and mammillary body of both behaviorally tested animals and in separate groups sacrificed at end of 3rd bout of thiamine deficiency (7th month); 3) Determine: i) thickness of white matter and frontal and parietal cortex; ii) neuronal density in frontal and parietal cortex and CA 1 & 3 sectors of hippocampus; iii) number of cholinergic neurons in medial septum, vertical limb of the diagonal band, and nucleus basalis and noradrenergic neurons in the locus coeruleus; iv) choline acetyltransferase, muscarinic receptors and synaptophysin binding densities in cortex and hippocampus; and, v) presence of Wernicke-type pathologic changes in thalamus, mammillary bodies, and brainstem; 4) Determine which of the treatment conditions correlate with the behavioral, pathologic and biochemical disturbances.